Carney S L
Osteoarthritis Department, Lilly Research Centre Ltd., Windlesham, Surrey, UK.
Osteoarthritis Cartilage. 1996 Dec;4(4):251-61. doi: 10.1016/s1063-4584(05)80103-7.
To investigate the effect of diacetyl rhein (DAR) on the synthesis, turnover and composition of cartilage in an experimental model of osteoarthritis in beagle bitches.
Osteoarthritis was induced in mature beagle bitches by the transection of the cranial cruciate ligament. Six animals received DAR 20 mg/kg daily for 11 weeks. A matched group received empty capsules daily for the same period. At 11 weeks, articular cartilage was examined for the ratio of the 6:4-sulfated disaccharides of chondroitin and the tissue concentration of hydroxyproline and glycosaminoglycan. In addition, labeling studies were performed to estimate the effect of DAR on proteoglycan synthesis and turnover.
DAR had no effect on body weight or food consumption but induced a mild diarrhea and slightly increased the incidence of vomiting. DAR tended to reduce proteoglycan synthesis, however, DAR did reduce proteoglycan turnover in the femoral cartilage. DAR produced changes in the composition of the osteoarthritic cartilage that could only partly be accounted for by changes in hydration and/or swelling. In addition, it was noted that induction of osteoarthritis increased the ratio of chondroitin 6-sulfated to chondroitin 4-sulfated disaccharides; DAR reduced the ratio in tibial plateau cartilage from osteoarthritic joints compared with untreated tissue from osteoarthritic joints. DAR showed moderate reduction on the biosynthesis of proteoglycans. DAR also produced a reduction in proteoglycan turnover from all anatomical areas compared with non-treated controls in both the lateral and medial femoral condyles.
DAR was well tolerated by the experimental animals, but did not produce significant changes in the synthesis or turnover of proteoglycans. The slight reduction in proteoglycan synthesis may prove to be biologically significant after chronic dosing. DAR's effects on the hydroxyproline and glycosaminoglycan content suggest, however, that it must influence the swelling of cartilage and loss of glycosaminoglycan. This indicates that small changes can translate, to significant differences in cartilage composition over an 11-week time period.
在比格犬骨关节炎实验模型中研究二乙酰大黄酸（DAR）对软骨合成、更新及组成的影响。
通过切断前交叉韧带在成年比格犬中诱发骨关节炎。6只动物每天接受20mg/kg的DAR，持续11周。一组配对动物在同一时期每天接受空胶囊。11周时，检查关节软骨中软骨素6:4-硫酸化二糖的比例以及羟脯氨酸和糖胺聚糖的组织浓度。此外，进行标记研究以评估DAR对蛋白聚糖合成和更新的影响。
DAR对体重或食物摄入量无影响，但引起轻度腹泻并略微增加呕吐发生率。DAR倾向于降低蛋白聚糖合成，然而，DAR确实降低了股骨软骨中蛋白聚糖的更新。DAR使骨关节炎软骨的组成发生变化，而水合和/或肿胀的变化只能部分解释这些变化。此外，注意到骨关节炎的诱发增加了硫酸软骨素6-硫酸化与硫酸软骨素4-硫酸化二糖的比例；与未治疗的骨关节炎关节组织相比，DAR降低了骨关节炎关节胫骨平台软骨中的该比例。DAR使蛋白聚糖的生物合成适度减少。与外侧和内侧股骨髁的未治疗对照组相比，DAR还使所有解剖区域的蛋白聚糖更新减少。
实验动物对DAR耐受性良好，但未使蛋白聚糖的合成或更新发生显著变化。长期给药后，蛋白聚糖合成的轻微减少可能在生物学上具有重要意义。然而，DAR对羟脯氨酸和糖胺聚糖含量的影响表明，它必定会影响软骨肿胀和糖胺聚糖流失。这表明在11周的时间段内，小的变化可能转化为软骨组成的显著差异。
